病毒性疾病长期以来是人类健康的巨大威胁。病毒是一种具有强生存能力、强变异能力的微生物群体。历史上，世界很多地区都曾遭受到鼠疫病毒、霍乱病毒及天花病毒等的袭击。在医学科学发展迅速的 21 世纪，非典病毒、禽流感病毒等依然严重威胁人类生命及健康。 寨卡病毒（ZIKV）近年来在中南美洲等地区快速扩散，多项研究表明寨卡病毒感染与胎儿小头畸形症和成人格林巴利综合征紧密相关。目前，尚无有效的疫苗或小分子药物被 FDA 批准上市。人类免疫缺陷病毒 1型（HIV-1）是从欧洲和美洲分离得到的致病能力较强的艾滋病毒株，根据病毒感染趋向性的不同可分为以 CXCR4 为辅助受体的 X4 型病毒、以 CCR5 为辅助受体的 R5 型病毒、兼以上述两种辅助受体的 X4R5 型病毒三种类型。 药物分子设计是假设驱动的发现过程， 分子模拟已成为药物设计及药物靶点相互作用研究中不可或缺的重要研究工具，包括分子对接、分子动力学模拟、结合自由能计算等。利用计算机模拟手段系统性筛选和设计药物、深入研究药物分子与靶点蛋白间的相互作用在抗病毒药物研究方面具有重要意义。本论文围绕抗 ZIKV 及 HIV-1 药物设计， 展开了基于分子模拟的理论计算及病毒感染实验验证的多角度探索。 研究以 ZIKV 复制的 NS3 解旋酶及 HIV-1 入侵的 CXCR4 辅助受体为研究靶点， 采用分子对接、 绝对结合自由能计算、 抗体竞争性结合实验、特异性荧光探针设计、病毒感染实验等多种技术手段， 筛选出了两类具有新型化学骨架结构且活性良好的抗 ZIKV 小分子抑制剂先导化合物， 证实了其对病毒复制过程的阻断作用， 并进行了结合模式分析与结合自由能计算； 通过建立原型分子的新活性构象模型进行了抗 HIV-1 小分子的虚拟筛选，并对现有多类小分子及多肽 CXCR4 抑制剂的结合模式及亲和力进行了深入计算分析；此外本研究首次将基于 PDLD/S-LRA/β 的结合自由能计算应用于针对 NS3 及 CXCR4 蛋白的研究中， 加深了对药物分子抗病毒机制的理解。综上所述，本研究系统性地建立了靶向 NS3 解旋酶的抗 ZIKV 及靶向 CXCR4 的抗 HIV-1 抑制剂计算筛选、 实验鉴定及分析体系， 完成了多个先导化合物的筛选鉴定及与受体蛋白结合模式的机制研究， 从而为后续抗病毒药物的发现或改造研究提供了重要的理论依据和指导。
Viral infection is a significant threat to human health. Virus is a microbialcommunity with high potential of survival and mutation. Many countries and areas in theworld have been affected seriously by widespread transmission of plague, cholera, andsmallpox viruses. In 21st century, SARS and avian influenza still threaten human healthsignificantly despite the rapid development of medical sciences. Zika virus (ZIKV) hasbeen spreading rapidly in Central and South America in recent years. Several studies haveshown that Zika virus infection is closely related to Microcephaly in fetus and GuillainBarre Syndrome in adults. Currently, there is no effective vaccine or small molecule drugtargeting Zika virus that has been approved by FDA. Human Immunodeficiency VirusType 1 (HIV-1), a highly pathogenic strain of HIV according to infection tendency, wasoriginally isolated from Europe and American. There are basically three HIV-1 subtypesbased on viral entry process: X4 virus with CXCR4 as co-receptor, R5 virus with CCR5as co-receptor, and X4R5 virus with both as co-receptors. Computer-aided rational designis a hypothesis-driven discovery process. Molecular simulation has become an importantresearch tool in drug design and drug-target interaction studies, including moleculardocking, molecular dynamics simulation, free energy calculation and othermethodologies. It is of great significance to screen and design drug molecules and studymolecular interactions between drug molecules and target proteins systematically bycomputer-aided simulations.This research focuses on theoretical calculation and experimental identification ofanti-Zika and anti-HIV molecules and protein-target interactions. Molecular docking,absolute free energy calculation, competitive binding analysis, specific fluorescent probedesign and antiviral biological tests were applied to study ZIKV NS3 helicase inhibitorsand HIV-1 co-receptor CXCR4 inhibitors. By combination of virtual screening,experimental verification and further theoretical analysis, novel ZIKV inhibitor leadcompounds were discovered and analyzed for their inhibitory mechanism and molecularbinding modes. In the study of HIV-1 inhibitors, a new molecular docking prototype wasestablished to screen novel small molecules targeting CXCR4. Furthermore, bindingmode analysis and free energy calculations, in combination with fluorescent probe-based competitive binding experiments, were performed on diverse kinds of well-knownCXCR4 small-molecule and peptide inhibitors, providing both theoretical andexperimental basis for future drug design, modification and preclinical studies. To sumup, this study systematically established screening, identification and computationalanalysis for anti-ZIKV and anti-HIV novel inhibitor molecules. Discovery of leadcompounds and detailed binding mode analysis will benefit future antiviral drug researchand development.
